HUE033499T2

HUE033499T2 - Use of combination preparations comprising antifungal agents

Info

Publication number: HUE033499T2
Application number: HUE07718439A
Authority: HU
Inventors: Christian Noe; Marion Noe-Letschnig
Original assignee: Christian Noe; Marion Noe-Letschnig
Priority date: 2006-05-12
Filing date: 2007-05-10
Publication date: 2017-12-28
Also published as: US8815925B2; RS56044B1; EP3192507A1; CY1119094T1; US8552042B2; EP2018164B1; ES2627268T3; WO2007131253A3; CA2651726A1; CA2651726C; SI2018164T1; WO2007131253A2; NO342103B1; NO20180083A1; CN101484162A; DK2018164T3; US20140030312A1; PL2018164T3; NO20085181L; US20090208558A1

Description

Use of Combination Preparations,: Comprising Antimycotic»

The invention relates to the us® of combination preparations, comprising antimycotic», for the treatment of Candida mycoses. Yeast, primarily Candida spp. (Candida albicans) usually are op-portunistic pathogens which become pathogenic only when the oys-temic or the local immune defence is impaired (e.g, oral thrash in Ήΐν patients, leukemia patients, under chemotherapy, in babies ; intertriginous ecrema in Diaoer.es mellitu») , An exception is vulvovaginal Candida mycosis of an otherwise healthy woman. However, also with the vaginal esndiciose there ate a number of factors which cause an increase in the virulence of the pathogen, and which, in case of a respective personal disposition, may change from an asymptomatic colon nation to a symptomatic disease .

The vulvovaginal mycosis is a very frequent disease which has continuously increased over the last years.. According to recent estimates, three out of four women get a vaginal mycosis at least onoe in their lifetime. In 5% of the cases, the disease takes a chronic-recurrent course which often constitutes a severe: subjective impairment for the afflicted patient. Treatment of the vaginal mycosis is particularly difficult during pregnancy, since in this case there exist particularly promoting factors on. the side of the patient, while on the other hand the possible therapies are considerably restricted and, thirdly, a therapy is absolutely necessary since otherwise the newborn baby will be infected during birth.

Oropharyngeal thrush diseases in turn pose a problem not only in newborns with their immature immune system, but also in patients with an impaired immune defence, such as HJ.V patients, patients undergoing chemotherapy and patients suffering from malignant hematological tumours. As has been mentioned, it is known that infectious diseases attack debilitated: and immunosuppressed humans particularly easily, wherein - as is the case in many diseases caused by Candida spy. - harmless symbionts become pathogens .

Nevertheless, this fact has not been sufficiently mechanistically considered in the therapeutic concept. So far, no drug or combination of pharmaceutical substances in a drug has received a market authorisation by means of which the infectious- ness: of the pathogen on cellular level has declaredly been reduced or stopped by influencing physiological reactions of the pat lent in combination with a direct "attack'·' on the fungus.

At present, the therapy of cutaneous and mucocutaneous cun-dioiasi. s is exclusively effected by antimycotlcs which., depending on the respective dose, have a fungistatical or fungicidal effect and, depending on the active substance, are applied systems cal iy or locally.:

For the therapy of Candida mycoses, such as the thrush of the oral cavity or the vaginal mycosis, a plurality of drugs having an antimycotic effect has been granted market authorization, in most oases for the topical, yet also for the systemic therapy, the mechanism of the pharmacologic activity of nearly all of the pharmaceutical substances used is well known. Obviously, moat of the known mechanisms are geared to the infective organism (bacterium or fungus) itself, thus, a number of these pharmaceutical substances interferes In the orgosterola-biosynthesis (isoprene biosynthesis pathway) by inhibition. The pharmaceutical substance attempts to inhibit or kill the fungus via physiological processes that should differ from the husién metabolism as far as possible.

In WO 00/16353 A2, peptides derived from a i p h a -me t a η o c y test emulating hormone have been suggested for the treatment of handida vaginitis. EP 1 633 133 hi relates to compos!lions for the treatment of athlete’s foot in sportsmen. EP 0 592 348 Al discloses compositions for the treatment of ophthalmic diseases. WO 2005/1X7831 Al describes posaconazole-containing preparations for inject!Oh for the treatment of mycoses.

According to WO 00/43633 Al, antibodies to hydrophobic proteins have been suggested for combating Candida mycoses, OS 2003/181384 Al relates to administering trefoil peptides for preventing epithelial damage possibly caused by infections. Local anti-inflammatory vaginal rinses containing benzydamine for the mechanical removal of a mass: of fungus have been suggested by Levy (Rev, fr, Gynecol. Dbstet. 84 (1889), 779-781), WO 95/17165 A relates to pharmaceutical compositions having improved aesthetics which are used to trahsm.it antimicrobial active s u o s t a n ce a.

In Kiefs, Infection and Immunity 62(4} (1994:), 1492---1500, it is shown that prossaglandine 12 is inni hising the attachment of Candid* albicans to endothel :Lai colls.

In Egffmann et al,. Expert Opinion on Investigatfonal Drone 11(3) :(2002), 1394-3734, the safety and efficacy of voriconazole la described1 which is a iriasolo anti my cot 1 c agent st; ruccu ra 11 y related to fluconaaole but having .unproved efficacy.

Krussewska et ai,, Acta Foloniae Pnarmaceufica, Polish Pharmaceutical Society, karssaw, PL 59 (2002 ), 436-439, character ice the antimicrobial activity of 'hion-antibiotic'' active substances. For Candida vaginitis, primarily in case of a chronic course thereof, the available spec trass of active agents does not yield any satis factory option of therapy. This is particularly true if the disease occurs daring pregnancy.

The molecular factors underlying the personal disposition are not known in detail, and accordingly, so far there is no drug, or combination of pharmaceutical substances in a drug, with which the infeetiousuess or the pathogen on cellular level is reduced, or stopped, respectively, by a cohcomitant direct ’'attack'" on the fungus and an influence on the physiological reactions of the patient. Therefore, there is an urgent demand for theraplee against Candida mycoses which so far cannot be successful iy treated by administering conventional antimycotics. In particular, Candida mycoses shall be treated which relate to infections of the mucosa, on the one hand, mainly vulvovaginal candidiasis, oropharyngeal candidiasis (oral thrush), and, on the other hand, Candida mycosis of previously damaged (macerated) skin, such as diaper dermatitis (diaper thrush), and intertrigi-nous ecsema. Such a therapy should also enable treatments of vulvovaginal mycoses in pregnant women which requires a particularly careful use of drugs,

Accordingly, the present invention relates to the use of a combina 1.1 on dr u g, coni a in i n g ~ an antimycotic agent, wherein said antimycotic agent is Clot-nmarole or Miconasole, and a non-steroidal anti-inflammatory drug (M3.AID) Having a sufficient CCXl-inhibition, defined by the exclusion of compounds having a C0X1/C0X2 ratio (1350, microM) of > 20, wherein said OSblD is Diclofenac or mefenamic acid;, for use in the topical treatment of Candida mycoses selected from vuivovagxnu i candidiasis, oropharyngeal candidiasis {oral thrush) , diaper de .ana lit is (.diaper thrush) and iutertriginons ecreme, wherein said combination drug is prepared as a / an o i η n ·· ment, cream, vaginal suppository, vaginal, buccal or sublingual tablet, powder, or aerosol,

The: mycoses to foe preferably treated according to the invention have in common that not only the pathogen, but also the alti letérd organism (the patient) contributes considerably to the generation of the disease and to the maintenance of the infection, Apart from the fact that, the tendency to contract a disea an is basically higher in patients having an. impaired immune system, it is the mechanisms of infectlousness which are of particular relevance in this connection. Only in recent years, such concepts have increasingly been investigated in the research rege r d i n g a. n t i -1 n f e ct ive agents.

The first step deterntining the infectiousness when a cell is afflicted by a pathogen consists in the pathogen's attachment to the plasma membrane of a cell. In general, a plurality of different systems of adhesion molecules, i.e, celi-celi-i. attractions, have become known for such an. attachment. The general ability of pathogens for adhering to epitheliums and edothe1iums also occurs via the Interaction with adhesion molecules, For certain pathogens, for certain organs and for certain clinical pictures of diseases, a special set of involved adhesion molecules is to foe erpected. For infections In general, and mycotic infections in particular, however, adhesion factors which are only partially involved have been published, without, however, having been summarized in a comprehensive concept, or without having been, introduced into a therapeutic concept. The present invention is based on the finding that the same adhesion molecules which play a decisive part in the course of the coagulation of blood during the adhesion, ox the thrombocytes and whose expression is induced by derivatives of the arachidonic acid metabolism (inter alia von Wfllefofahd factor, vitronectin, fibronectin, intogrins), arc induced during the transformation to pathogenicity by accompanying factors or the pathogen itself and, subsequently, are atilimed for the adhesion by the palmar i-1y οpoortunistic patπogens .

It has been known for quite some time that under the influence of prostaglandins, Candida fungi undergo a transformation of the!t shape from búddá no shape to hyphen shape which is ac-companied by an increased growth, Prostaglandins are dóri veti vea of srácaidonic acid. The active principle of the class of phar·· macacti.oa 1 substances of the MSAIDs, which arc mainly used for the treatment of inflammatory and rheumatic diseases, primarily consists in the inhibition of the prostaglandin biosynthesis.

The aniinonce of MSAlOs on the growth of fungi has been demon·· strated in in vitro experiments (Scott et ai . , Ant i.mi crob. Ag -Chemoftierv 3s (12} (1995), 2610-2614; Tarig ét ai,, Antimicrob, hq, Ghemother, 39 -(.12) (1995), 2615-2619; Yueesoy et al, , J,

Chemother . 12 (2000), 365-389), In this coiábinátlón w 11r} an t 1mycotic agents, an increase in the anti •mycotic effect has occasionally been observed, yet the term ''·paradox effect'' has been explicitly· established for this, since, in vitro, at some concentrations and in some combinat 1ons, instead of an inhibition there results an increased growth (Arai et al,, Mycoses 48 (2:005), 38-il) , Thus, the effects of I bop rőten in combination with various antimycotics have been very varied (Tarig et ai., 1995) , FG.aQöhaeola-sensitive strains of €h albicans have not shown an improved response to a combination of Xbuprofen with Fluconaxoie in the in vifro-system (Aral et ai,, 2005), In summary, the results of the m-vitzo tests have shown that,· based on the growth of the fungus, the effects depend on the respective fungus strain used, yet that from these no conclusions can be drawn on the medical efficacy at the site of the mycotic infection, neither in the one (positive) nor in the other (negative) direction.

Since usual in—vitro experiments regarding an anti.-mycotic activity of certain substances or substance combinál:ions do hot take the physio log road, response of the host into consideration, in none of these in-vitro projects, the part which the cell-cell adhesion plays in the infection in general, or changes occurring in the host's epithelium or endothelium, respectively, can have been addressed in the least,

Moreover, in the relevant literature, the therapy resistance occurring in the treatment of chronic-recurrent Candida vulvovaginitis i.a. has been attributed to the increased occurrence of certain Candida subspecies (without, however, offering a conclusive total concept), Yet, especially for these subspecies, no in vu t: ró*· result s whatsoever are available.

In case of Candida, in fact the trees .tormási on oh one greets habit from the budding form to the byphae form is a prerequisite for the .Layer-typo overgrowth, this clearly intensifies the pathogenicity of the pathogen. The formation of the hyphen in turn is promoted by prostaglandin E2 which is also formed by the patient’s endothelial cell/epithelial ceil during the inf1amma-tory process, also the increased mucus formation of mucous membranes occurring during the inflammatory process plays a part in this pathological process.

Under certain promotive conditions in the microenvironment, such as, e.g,f an impaired immune situation, yet also in case of suitable hormonal conditions or a patient’s: genetic disposition or, on the other hand, due to quorum sensing:, some pathogens, such as, in particular also Candida species, are capable of overgrowing the affected sector of the skin, mucosa or endothelium by forming a closed layer, This not only aggravates the pathological process; due to the transformation of the growth habit, also the pathogen’s vulnerability by local treatment methods changes. In this growth habit, the pathogens practically can no longer be attacked by the usual locally applied antimycotic agents , Chream, fleet ion occurs , and it becomes necessary to change from a local therapy to s systemtic therapy. A systemic antimycotic therapy, however, often Constitutes a great strain due to the spectrum, of side effects of many oneimycocic agents and, in case of pregnant women, it is completely impossible because of teratogenic effects. Yet;, even under systemic therapy, the chronic-recurrent vuivovaginitis and colpitis caused by Candida spp. (with Candida albicans and Candida glgbrata being the most frequent pathogens) often are not cured, and many female patients suffer from several recurrences each year,

The present invention is based1 on the so far unknown finding: which, however, is central with regard to infectiousness that, when attaching to epithelial cells (or to endothelial ceils, respectively), yeast fungi Use a r a ch i do n i c - a c i. d -b a s e d mechanisms of the body itself, by which the organism usually reacts to cell-damaging' novae . A ra choc on ic acid is known to be converted; on the cyclooxygenase pathway not only to prostaglandins, but also to thromboxane and prostacyci.ine, Under the influence of thromboxane, the thrombocytes aggregate and adhere to the damaged membrane so as to seal the latter. In order to enab 1 e an adhesion, different adhesion molecules are not only presented by the 1hrorr-bocyte; also the endot nei 1 am specifically prepares itself for the adhe-alop. On molecular level, these effects are primarily mediated via adhesion molecules, such as, e,g., von Wiilebrand factor.

The processes taking piece during: the adhesion occur temporally adjusted in the thrombocyte and in the vessel endothelium. If is mainly too derivatives of the araonidealc acid cascade which plat·· a decisive role as adversaries in the process of blood co-agnation; besides thromboxane which causes the aggregation of rhromOocytes, it is the "adversary" prostacyclin which prevents the reactive process from spreading excnssiveXy. The biosyotbe-sis of thromboxane and prostacyclin is mediated by different en-ryme s.

Thrombosane is synthes1zed via e y c 1 ο o x y ge n a s e -1 (COX 1}, prostacyclin via cyciοorygenase-2 (C0X2}.

An essential element: of the mycotic: infection consists in that the fungus/host interaction comprises a series of mechanXs-" tic analogies to the thrombocyte/endorhelium interaction. Primarily, this means that inflammatory processes occur in the host cells either before or simultaneously with the mycotic inrecsion, 1.e. the transformation of apathogenic, or possibly pathogenic, respectiveiy, to pathogenic causefive agent (e.g. Filler et a1,, Inf. Immun, 64 (1996), 2609-2617; Cannora et ai,, J, Inf, bis, 186 (2002), 389-396), uhieh are controlled via the arashldonic acid cascade, or that the adhesion of the fungus is rendered possible at ail by previous: rnf 1 ammatcry processes in the host cell. On the part of the fungus, adhesion of the fungi to the heat ceils occurs via the hyphae, on the part of the host call,, it is substantially effected via an arachiconic-acid-dependent mechanism, utilising the adhesion molecules expressed under these conditions at the host cell, such as, e,g., von Wiilebrand factor, vitronectin:, f iProneotin or various integráns,

Providing Diclofenac and mefenamic acid as at epithelial cell or endothelial cell adhesion inhibitor in the combination preparation according to the present invention is, therefore, an essential element for the antimycotic agent to become effective at all in the infected area of the Candida mycoses to be treated according to the invention. The nature of the epithelial cell or endothelial cell adhesion inhibitor as such is not critical, the selection is generally dretcted by galenic aspects for (promoting an) optimal activity of the antimycotic agent, Therefore, antimycotic agent and epithelial· cell or endothelial cell adhe·· a .Lon inhibitor are opt Imi red in the combination preparation also on the basis of their physico-chemical properties. This adhesion inhibitor according to the invention exerts an influence on the arachidonic acid metabolism so that the inventive combination is capable of synergistreally acting oh the mycotic infection: at the site of infection and by utilising the patient's endogenous arachidonic acid mecnanisms .

Therefore, the epithelial cell or endothelial ceil adhesion inhibitor is selected from - a non-sroroidel antiphlogistic agent {bS.AID) , namely Diclofenac or mefanemic acid:, with a sufficient Gödi inhibition which, on the one hand, results from the intrinsic activity and, on the other hand, from the extent of the selectivity of the inhibition of COXI relative to COX2 under therapeutic conditions. This means tha t all the subs lances which exhibit a more selective COX2 inhibition than, e.g., beioxicnm or Diclofenac, are not suitable as defined by the invent.ion (such as, of course, also all the substances which do hot exhibit any activity or effects on the a rácaidonic acid metabolism;, The selection in terms of number is effected, e.g., by stating the COXI/00X2 ratio of the ICSO values, yet this will differ with the method used. Suitable compounds may, e.g., be defined in terms of numbers in accordance with the date supplied by K, Brute et al. {Deutsches An·· teblatt 97, (26) 2000, A-1 BiS/B-lalB/C-i 4 24) by a C0X1/C0X2 ra tio (1050) of □ 20.

These MSAIDs have at present already a market authorization.

The NSA1Ds contained in the combinak ion preparation according to the invention are inhibiting the aggregation of thrombocytes* This is not only effected1 via the suppression of the expression. of suitable adhesion molecules, but mainly also by triggering/increasing the shedding of these surface molecules.

The inventive use of such compounds in combi nation with an antimycotic agent thus both prevents the infection, and also prevents the "boosting" of the infection triggered by inf1ammatory processes occurring in the course of the infection.. The finding that such a complex: process as the adhesion of o. fungus to the endothelium of the host can be influenced by active substances of a well-known class has not been Known so far and forms the basis of the combination preparations according to toe innantion by which the surprising clinical results according to the pro-·· sent invent!on could be achieved, in particular in case of the preferred Candida mycoses described which so far could not be treated or could be treated only with difficulty.

The inventive combi cati one of pharmaceutical substances are intended for topical application (at mucosae or also on highly inflamed skin areas, such as in case of diaper thrush, and in-tortrigincus eczema) for treating mycoses (vulvovaginitis oropharyngeal candidiasis (oral thrush), diaper dermatitis, inter-trignions eczema) and, as mentioned before, consist of an antimycotic agent and a non-steroidal antiphlogistic agent (PSMD) having a sufficient COXl-inhiPition, defined by the exclusion of compounds having a COX! /COX2 ratio (105.0(, microM) of > 20.

Yet, not all the MS.hIDs are suitable compounds in the combination preparation according to the present invention, since PSATDs, depónbind on their profilea (COX1-inhibitor or COX 2-inhibifor), generally have a promoting (COX2) or inhibiting effect (COX1) on an adhesion. For this reason, the treatment of dermatologic diseases with a combination that contains a seiec-t i ve COX2-inhrbitor (such as, e.g,, disclosed in US 2001/0014129 A) la wrong with: regard to the therapeutic aim of the present invention, 1,e, causing the reduction of the adhesion in the patient's endothelium or epi she id cm. Highly selective COX2 inhibitors or anti-inflammatory agents without an activity on the arachiconic acid mechanism (such as, a„g,, benzy-damine (Riboidi et ai ,, Br, id Oh a rmacol, 140 (2003), 377-383); are no relevant compounds as defined by the present invention>

The selectivity of the PSAIDs Diclofenac and mefenam re acid is, e. g, , expressed by the ratio of the ?.C SO {miorod) C0X1/C0X2, yet the values will generally depend on the pharmacological test systems used and will differ greatly, and therefore, according to the invention, the values are determined In terms of numbers according to the data given by K, Bruns et ai. (Deutsches Arον emiatt. 97, (26) 2000, A-1818/B-X538/C-1434) ,

What is essential for the therapeutic effectiveness is a sufficient COXi- inhibition (absolute value of the 1C SO- at the respective administered therapeutic dose, Post of the NBAIDs are mixed COXl/COXi-inhibiters, As long as there exists a COKI inni- hátion, the C0X2-inh,ihl.t.ion it very wei looms (because of the suppression of pain) . Therefore, HSA IDs without or with only a alight preference ox the COX2 are substances to be used recording to the invention., hot suitable are, however, (highly} selective COX 2 -inhibitors which do not have a COX 1. effect or have on -1 y an insufficient COX1 effect under therapeutical conditions (dosages}, On the contrary, the selective COX2 inhibitors may even negatively affect the clinical picture and, therefore, ate to be avoided within the scope of the therapy according to the invention, therefore, according to the inversion NSAXDa which have a value of > 20 for the COXl/COXS-ratio (based on the above-cited 11 re mu re) are to be excluded (for highly-select ive COXx-inhibitors with a market author!cation, values of mote than 100 result, e . q . Ceiecoxib, Rofecoxib, VaXdecoxih, Etorlcoxih).

The particular significance of the combination according to the invention of an antimycotic agent and Diclofenac or mefanemic acid will directly depend, on the extent of the effect of the second component which primarily contributes to the therapeutic effect by en adhesion-suppressing effect on the patient’s endothelium and/or epithelium. Therefore, it is of partionfar importance: to consider that the term '’skin diseases" covers a broad range of shin tissues of completely different structures; from an adult/s nail to a baby's mucosa. What is common to all the diseases which have beer .mentioned as preferred indications for the combination preparation according to the present invention (vulvovaginal candidiasis, oropharyngeal candidiasis (oral thrush) , diaper dermatitis (diaper thrush) and. infertrigxnous ecsemu) is that it is the surface of the afflicted tissue sec-fora which, due to the expression of corresponding adhesion molecules, enables an adhesion of the fungal colonies. The combination preparation according to the invention serves for the therapy of mycoses, preferably for the therapy of Candida mycoses which, typically, occur on the aforementioned skin types, i.. e. mucosae of the genitourinary tract and the oropharyngeal region as well as on previously damaged (macerated, injured, inflamma-tor11y c h anged} enter skin,

Accordingly, it is not a subject matter of the present invention to carry out a. therapy of dermatophyte diseases (Dr-1 390 031-Bl.} with the combination preparation described, diseases víhieh often colom?e the kor®tic layers of the epioermis, $mc« there the contribútion to the theropentic success which is pro-vi dec by preventing the adhesion of the fungus to the hősies epithelium is markedly lower and;, therefore, the inventive effect will not occur, This also holds, e. q,, for the treatment of my~ cos on of the nails (Wu 2000/018821 A1} , since herei too, the use ox the inventive combination preparation is hot purposeful since, here, too, the surprising synergism of the two components in the inventive preparation will not occur (to the inventive extent}? in particular because in this instance the state or the epithe-linm is of minor importance compa red to the part icularities of the therapy of these diseases, in Particular the poor "accessa-biiity" of the therapeutic agent.

For the topical therapy according to the invention with the described combination drug on mucosae or previously damaged outer skin, respectively, according to the invention not only significantly lower concentrations of the active substance: will basically suffice as compared to diseases of the normal or more kera t mined outer skin and its adnexa, also a signif icant improvement of the subjective and objective disease symptoms will occur within a substantially shorter time (from minutes to a few hours vs, from days to weeks when applying the treatment methods: common at present). Thus, the particularly lew dosage of the ad-n e s i ο n - i η n i 0 r t i n g active substance Is a substantial advantage with the present invention, This rapid start of the effectiveness is solely caused by the procedures on the skin or mucosal surface that has been changed due to inflammation and, therefore, can be forecast or determined in principle neither by in yiftro'·-tests nor by examine 1 ions on the non-1 nflamed outer skin. Since the greatly enhanced effect is caused solely based on mechanisms occurring on the exposed surface of the respectively afflicted organ (expression and rejection of the adhesion sites), particular iy also this effect cannot foe determined by in-vitro experiments, and, in fact, it. has been shown that in -vitro experiments, depending on the fungus strain used, the dosage and the combinations of pharmaceuticai substances used, have yielded the most cent fadIctory results, In this context, it is also notable that the combination of Pluconasoi with Iboprofen in Finoona-cl-sensitive strains has not shown any synergistic effect in the in-virro experiment (Aral et a1,, 2005}» The effect obtainable with the combmat 1 on preparation of the invention therefore also cannot toe de n ved in this way (via in -vi tro experimenss} , Also in ease of a systemic administration of the inventive combination preparation,, in particular of the NASI to chosen according to the invention, fox pharmacokinetic reasons a respective effect is not to toe expected even at a common dosage, and much less so at the low dosages which are made possible with the present invent Ion»

The required low dose is also due to the fact that the epithelial coll or endothelial cell adhesion inhibitor exerts its effect both on r.he fungus and on the epithelium: of the patient. Thus, also a treatment of breastfeeding: babies and of prequant: women is possible>

Thus, the effect of the inventive combination, of oharmaceu-tatai substances is based on 1. suppressing pathogen, growth, 2. suppressing adhesion of the pathogen on the host cell, 3. suppressing the acute inflammation and: pain symptoms by inhibiting the prostaglandin synthesis on the part of the afflicted organism, i. preventing the generation of the prometlve factors in the local environment, i.e. the adhesion to the host ceil upon transformátion of the pathogen and, thus, preventing an aggravation of the clinical picture, and S. interrupting the pathogenetic mechanism in ease an agqrava·-tion/chronification has occurred, wherein 2,-5. are mediated toy Diclofenac or mefenamic acid (which interferes in the arachidonio acid: cascade) and 1. is mediated according to the mechanism of activity of the antimycotic agent used,

This allows for a therapy concept which is completely new as compared to the prior art, which - apart from the effectiveness which by itself already is surprising in (chronic-recurrent; vulvovaginal candidiasis, oropharyngeal candidiasis (oral thrush), diaper dermatitis (diaper thrush) and intertrig!nous ecsema - is, moreover, characteriseo by the following advantages and effects compared to the prior art: 1. possibility of a local therapy, 2, in case of chronification, marked reduction of the tendency to recurrence, 3, highly accelerated onset of offset,, 4 . aignj.fi easily reduced dosage of the antimycotic a gen t , and 5, immediate pain relief. ltd 1 < In case of promotive factors, in particular also for an agyravation/ohronificstion, e . g., an imoonosuppreseton,· tomors a 1 and genetic factors, according to the prscent invention the pathogenetic mechanism on which the disease disposition is based1 is inhibited, The disease can be centrelied, and cured, respectively, without a systemre therapy. Avoiding the changeover to a systemic therapy (which often is effected by using pharmaceutical substances that are a greater strain) is important both in case of an existing pregnancy and in patients suffering from HIV, leukaemia, or under chemotherapy and markedly reduces the strain on the patient, according to both subjective (compliance) and objective criteria (strain on the metabolism}, The chronic-recurrent vulvovaginitis in pregnancy can hardly be controlled by means of the conventional therapy regimen, since the systemic application of the orally applicable antimycotic agents i Fiucosv* atoX) is absolutely courier~indseated in pregnancy.

Ad 2. Also in Case of a chronic-recurrent course of the disease (in particular in case of vulvovaginitis due to Candida infections;, the underlying pathogenic mechanism is interrupted, and a topical therapy is rendered possible instead of the long-lasting systemic therapy.

Ad 3. Compared to the hitherto usual therapy, the onset of the effect is greatly accelerated, i.e, it occurs within minutes (:vuIvovaginitis) to hours (diaper thrush) as compared to days to weeks (or not at all) in conventional therapy.

Basically, the difference resides mainly in the duration cf tree invent, the therapy regimen proper will, however, first of all depend on the half-life of the pharmaceutical substances used. The difference may, e,g,, be elucidated, by way cf the chrοn1c-reeurrent vu1vovaginitis;

Use according to the invention;

Initial therapy: 3 ·· 5 x dally local application of the drug combination as an ointment, or by means of another locally applicable drug formulation for three he five days; in case of recurrent affliction; 2-3x daily local application for one day is sufficient (the recurrence-free intervals will always become longer with continued application.) ,

In contrast, the present therapy regi men (ecu see:: Leitiinien dor deutsenen Gesei ischafr fur Gynakoiogie und G g parts hi If e) : Initial therapya

Fluconazol ISO mq orally, 1 or 2x/week for 4-6 weeks, subsequent ly ΐ Fluconazol ISO eg orally, lx/2 weeks for 2-3 snonths, subsequent ly FI sconasol ISO mg orally, lx/3 weeks for 4~€ mouths.

After discontinuation, about SOI of the cases become recurrent, as before the therapy.

Ad hí Due to the potcutlating effect, the total dose of the antimycotic can be markedly reduced, in ease of the uncomplicated vulvovaginal mycosis, one can assume a by at least 50% reduced total dose due to the reduced treatment period, in the otopharyngeal mycosis, the reduction may be up to 66%,

Ad S; With the often very painful acute clinical pictures, fey the simultaneous topical application of MSAID with the antimycotic agent, an immediate pain relief and detumescence with missing to minimal total strain on the organism is achieved with the USAID (non-steroidal antiphlogistic agents) which, systemi-cally applied, are net free from side effects. As has been mentioned, the treatment according to the invention is based on the finding that the expression of certain adhesion moiecui.es at the tissue surface of the diseased organism or organ, respectively, constitutes a basic prerequisite for the colonisation by yeasts. The combination of conventional antimycotic agents with epithelial cell or endothelial cell adhesion inhibitors therefore di.-reotry interferes in the pathogenetic process. As has been mentioned, epithelial cell or endothelial dell adhesion inhibitors are substances which exacerbate or prevent, respectively, the adhesion of the pathogens to epithelial and/or endothelial cells and the formation of a layer-shaped colonization of the afflicted epithelial or endothelial sector. From the nature of the reopen sib ie adhesion molecules it results: that their expression ie prevented by active substances which interfere in the prostaglandin metabolism in a certain way, From the inventive combined application of ant imycofu ca U y effective substances and epithelial cell or endothelial ceii adhesion inhibitors, there results a potentiation of the therapeutic effect, The duration of treatment is greatly shortened, and a local treatment becomes possi- bie also in those cases in which so far exclusively a sysremic therapy had chances of success - Moreover, this type of a combi -cat .5. on of pharmaceutical substances also is el feet: ive in cases which are completely t h e v a p y ~ r e s i s t a n:: to drugs available at present ,

Therefore, the subject matter of the invention is the use of the inventive combinations of pharmacentical substances for the topical application on mucosae and on greatly inflamed and/or trace rated skin areas for the treatment of mycoses, preferably those caused by Candida spp, (vulvovaginitis, oropharyngeal candidiasis (oral thrush), diaper dermutltis (diaper thrush), intertrigo nous ecrams),

Application of the inventive combination preparation is ex-· ofusrvery local (ointments, vaginal tablet, vaginal suppositories etc.) to skin and mucosae. The dosage of the antimycotic agent (pelerabiy Ciotrimaroi) is effected at the concentration hitherto common, yet it follows that the daily total dose is halved, and the total treatment time is markedly reduced (from 7 to 2-3 days), The HSAID is admin ratered at 1/5 to 1/100 of the daily maximum done as an admixture to the ointment/vaginal tablet etc >

During the topical therapy with an inventive combination of pharmaceutical substances, as mentionod above, the total amounts of active substance that are substantially lower than those hitherto used in the antimycotic monotherapy suffice, and also the HSAID component is used at a significantly lower: concent ration than in all other indications for which: so far drugs of such substances have been used. Thus, also a treatment of breastfeed:;.no babies and pregnant women is possible,

Within a substantially shorter period Of time (from: minutes to a few hours, as compared to from: days to weeks when using the treatment methods common at present), a significant improvement of the subjective and objective disease symptoms will occur.

This rapid onset of the effect is solely caused by the processes at the surface of the mucosa and goes bach to the effect of aeach iconic acid derivatives triggered: at the art 1 inted or gar: surfaces ana, therefore, can neither be detected in in · vi::ro bests nor by examinations carried out on the normal outer skin.

The nature of the antimycotic active substance to be employed in the present combination preparation it principle is not érit ica i, as a rule, always an opt i mis ad combination pair will bo used, wherein the optimisation pr so a ally la based on. the antimycotic spectrum of the antimycotic agent, on the go lenien and on t n e physioo-euem ica 1 interact ions of tho antimycotic agent with tf·e epithelial cell or endothelial cell adhesion inhibit or,

Preferred are:, of course, those antimycotic agents which already hare a market authoriratIon.

Therefore, the antimycotic agent In the combination preparation according to the inception preferably is Clotrimaroie or Mi counsele,

Preferably, the combination drug according to the present invention is prepared as ointment, cream, lotion, gel, tincture, solution, vaginai suppository, vaginal, buccal or sublingual tablet, syrup, suspension, powder:, spray or aerosol, according to a preferred embodiment of the present invention, the combination drug may be provided on an inert carrier, in particular on a vaginal ring, a diaphragm or a tampon,

The invent ion will be described in more detail by way of the following examples without, however, being restricted thereto.

Examineiions and results on humans - case studies

So far, the therapy onecepf according to the invent ion has been examined on voluntary subjects within the frame of the doctors' freedom of prescription. Before the combination therapy:, ail the patients had received an unsuccessful antimyootio monotherapy ,

In the following, 6 examples will foe desert bed: vulvovaginitis: 3 cases diaper thrush: 1 cases oral thrash: 1 case

The treatment was by topical administration of suitable pharmaceutleal substance combinations on the skin, or on the mucosae of the genitourinary tract and of the oropharynx, respec-t iveiy.

The following combinations were used;

Vulvovaginitis :

Case X: h. female 41-year old patient suffering from chronic-recurrent Candida vulvovaginitis for years (> 10 recumenses/ yea r ;, otherwise healthy, pregnant, prior treatment (before the pregnanoy} both topical · CG.otr xmasoie, hyatatin) and aysLem.·· really {Fluconacoie, several times, also long-cerm therapy and therapy of the partner). Hasa ive deterioration with complete therapy resistance to local treatment with Ciptrimasole during pregnancyf extreme subjective comp1 a ints f or weeks , 'Syr··, findings; vulva severely reddened, clearly swollen, bloody ercoriations. Mucosa of the vagina and portié reddened. Massive vaginal discharge, smear findings: RAP 2., microbiol. swab, native finding; abundant leukocytes, fungus hyphen detectable in large masses, RG 3.

Therapy with an ointment combi tat ion of Clotrima -sole/Diclofenac-da

Single dose: 5 mg of Dicleter;ac-ha/ 20 mg of Clotrimazole Dosage regimen; initially (3 days) lx/day ointment strips of 2.5 cm locally applied in vulva and vagina, subsequently once per day, for 4 days.

The applied dose (total dose) of Diclofenac-Ha. is approri -mateiy 1/30 of the maximum cally dose at syotemio application.

The Clotrimazole dose is one half of the usual daily dose,

Findings af ter one week of therapy ( three days after termi -nation of therapy):

Patient subjectively free from complainis, (since beginning of therapy). Gyn, findings; vulva; results negative? mucosae of vagina and portio: results negative. Low-grade vaginal discharge. Microbiol, swab, native findings: no fungus hyphae detectable, isolated spores, dermal vaginal flora (lactobaciilil, MG I,

Follow-up: 6 months

Over the next three months, approximately 2 recurr eric res/month, one-day treatment as above in each case resulted in immediate freedom from complaints,

Following months; complete freedom from complaints, no new recurrences ,

Case 2: 43-year old female patient, suffering from chronic-recurrent Candida vulvovaginitis for years (> 10 recurrenees/year), otherwise healthy, prior treatment both topical (Clotrimarole, Miconazole) and system).ca.I ly (Fruoona tele, several times, also longterm therapy and. therapy of the partner/ , Acute exacerbation, low-grade improvement under therapy with Clotr inarole {8 days), partly extreme subjective complaints for 2 weeks.

Gyu. findings; vulva severely reddened, clearly swollen. dacosa of the vaginal and portio reddened. Massive vaginal, discharge ,

Initial, therapy; Clotrimazole/Dlelofenac (25/25 mg) supp. for 2 days f subsequently C1 otrimsnolo/D1 o 1 ofenac as ointment as described in Case 1, for 3 days.

Findings after 1 week: patient subjectively free fron complaints {since 2SiS day after beginning of therapy} , Gym findings; vulva results negative; mucosae of vagina and portio; results negative, Low-grade vaginal discharge.

Case 3; 12-year old female patient, suffering from chronic-recurrent Candida vulvovaginitis for years (> 10 recurrences/year;, otherwise healthy, prior treatment both topical (Clotrimazole, hysta-tin) and systemical (Fluconazole,, several rimes, also long-term therapy and therapy of the partner)„ Acute exacerbation, during this recurrence no pre-treatment, moderate subjective complaints for 2 days.

Gyp. findings: vulva reddened, swollen. Mucosa of the vaginal and portio reddened. Increased vaginal discharge,

Therapy: Clotrimasole/ Di.cloien.ee as ointment as described under Case 1 on the first day 5x/cay, frcm the 2na day onward 3x/day for a total of three days.

Findings after 1 week; Patient subjectively free from complaints (since: 18 hours after the beginning of therapy) , Gym findings; vulva results negative} mucosae of vagina and: portio; results negative. Low-grade vaginal discharge.

Case 4;

Diaper thrush;

Female breastfeeding baby, 12 months old, therapy-resistant eczema for more than 5 weeks at the labia majors (pre-treatment by paediatrician and dermatologists with:; zinc-oxide containing baby cream, hystatln-containiny cream, antibiotic (antibacterial) cream and powder, Ciotrimazoi-containing cream, corticosteroids. Under these therapies, continuous deterioration of the clinical picture.

Insp,: Pronounced reddening and swelling of the labia majors and per1anally.

Therapy with an ointment combination of Clotrima- zoic/Die1ofenac-N a

Single dose: ointment strips of approximately 5 cm in the evening (corresponding to approximately IQ eg of Diclofenac"" ha/40 mg ClotrimatoioV, complete healing over night. Subsequently , intes tinal sanitat ion with imystatin, oral suspend on .

Foilon™up (6 months}; no further complaints Case 5;

Diaper thrush;

Female breastfeeding baby, 2 months old, repeated diaper thrush (red papules;, leap: Small papules on the skin of the labia majors and in the perianal region.

Therapies tested: during various episodes, comparison of Clotrimazole cream with and without the addition of Diclofenac·"· t a a

Monotherapy: Cl or. rima role cream iCanesien} , single dose:. approx-imahely 25 mg of Clotrimazole

Combination; C1 oi.rzmazoie/Di defense-ha, single dose: approximately 5 rag of Didoienao-ba/20 mg of Clotrimazole.,

In both cases, local application, dosage; 4-5x/day,

Result:

Monotherapy: duration of treatment until complete disappearance of the lesions: 3 days.

Combination therapy: duration of treatment until complete disap-pea r ance of lesions: 24 hours,

Case 6:

Oral thrush:

Female breastfeed!no baby, 2 months old, repeated oral thrush (white lesions},

Insp. ; typical white furs on the: inner side of the upper and lower lips, diameter 4-5: ifim.

Therapies tested; during various episodes comparison of Miconazole gel with and without the addition of mefenamic acid. Monotherapy ; Miconazole ;Datear In geld , single dose 30 mg Combination; Mioonazoie/mefenamio: acid (gel).

In both cases local application, dosage: 2-3x/day

Single dose; approximately 25 mg of mefenamic ael.d/30 mg of

Miconazole

Re sul t:

Monotherapy: duration of treatment until complete disappearance of the lesions; 5 day»:

Combinál:on therapy: after 12 hours, significant reduction of the lesions* duration of treatment until complete disappearance of the lesions; 24 hours.

Summary of the results of the single case studies:: vul vo vug ini r. is ; The cases described were particularly severe oases of chfon i c-recur rent Candida vaginitis. Under monotherapy with Clotrimarole, the course or curing was highly retarded in the second case (8 days of intensive therapy, then improvement, but no freedom from complaints;, in the first and third cases no improvement could be achieved by conventional local therapy with Clotrimazole, By using the pha roe cent i cal substance combinations, an immediate marked improverrent of the subjective and objective symptoms occurred, and already on the second day of treatment, in all the cases the complaints completely disappeared.

Diaper thrush: Under Clotfimafole monotherapy, marked deterioration of the clinical picture in. the first case, healing after three days in the second: (mild.) case. Complete healing after the use of the pharmaceutics! substance combination, within 12 and 24 hours, respectively.

Oral thrush; healing with Miocnasole monotherapy after 4-5 days (criterion of diagnosis; no plagues visible any longer in the oral cavity), During: a second episode, treatment with the pharmaceutical substance: combinál ion, no plaques visible any longer after two hours.

These results show that in case of Candida mycoses which asre particularly difficult to treat, the combination preparation of the invention brings about a surprisingly rapid and comprehensive healing which could not be achieved with the monotherapy (antxmkycotic agent only),

The success of the treatment· was the clearer the more pronounced the initial findings had been.

Claims

COMBINATION CONTAINING ANTIMICOTICS: PREPARATIONS §mmm ^ zmk Patent; Compound medicaments comprising: * antimycotic agent, wherein the antimycotic agent is kiotrimazole m $ y mycenazole: s; and # # female contraceptive anti-inflammatory drug (MSAID), which has "anti-inflammatory" inhibition, which means that the chemical pathways characterized by COX1 / COX2 (IC50, microM) above 20 are excluded where the NBA © dfklöfenak or mefenamic acid for use in the treatment of Candlda mycorrhoids in the group consisting of a group of ligand vulgaris Candidiasis, oropharyngeafls Candidiasis (fungal infection of the oral cavity), pelvic dermatitis (diaper rash) and eczema, where the combination is medicated with ointment, cream, vaginal suppository, vaginitis, buccal or suiive tablets or powder or aerosol.

2, Combination Drugs for use in i. characterized in that the combination medicament is provided on an Inert carrier, a vaginal vaginal vagina, a diaphragm or a tampon.